ABNORMAL IRON DEPOSITION ASSOCIATED WITH LIPID-PEROXIDATION IN TRANSGENIC MICE EXPRESSING INTERLEUKIN-6 IN THE BRAIN

Transgenic mice, named GFAP-IL6, that express interleukin-6 in astrocy tes in the central nervous system (CNS) have a constitutive blood-brai n barrier (BBB) defect and develop a progressive neurodegenerative dis ease. Based on ultrastructural observations showing electron-dense pig ment in the brain of the GFAP-IL6 mice, we hypothesized that iron meta bolism was altered in the brains of these animals. Enhanced histochemi cal methods revealed abnormal iron deposition in the cerebellum from 1 month of age that worsened with progression of the disease. Immunohis tochemical analysis of iron-binding proteins (IBP) showed increased fe rritin immunoreactivity and a decreased signal from the transferrin re ceptor in symptomatic animals. Atomic absorption spectroscopy revealed a 40% increase of total iron concentration in the cerebellum at the s ymptomatic stage. In order to obtain evidence that accumulation of thi s oxidizing metal was toxic, we looked for the presence of oxidative d amage. Using the MAL-2 antibody, extensive lipid peroxidation (LP) was detected in the neocortex and the cerebellum in symptomatic animals. Ultrastructural analysis indicated lipofuscin deposition at the sites of neuro-axonal degeneration and abnormal iron deposition. These resul ts suggest that the IL6-induced BBB defect precipitates iron accumulat ion in the GFAP-IL6 mouse brain and that subsequent IBP regulation med iates protective responses. As these defenses become overwhelmed, the iron overload seems to promote LP, which may contribute to the neurode generation that ensues. This transgenic mouse model of IL6-mediated ne urodegeneration provides a unique opportunity to examine several aspec ts of iron metabolism in the brain, including its entry at the site of the BBB, its distribution through the IBP, and its mechanisms of toxi city.